Qing Qin1, Silvia Delrio2, Junxiang Wan3, R Jay Widmer4, Pinchas Cohen3, Lilach O Lerman5, Amir Lerman6. 1. Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 2. Università Vita-Salute San Raffaele, via Olgettina 58, 20132 Milan, Italy. 3. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA. 4. Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. 5. Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. 6. Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: Lerman.amir@mayo.edu.
Abstract
BACKGROUND: MOTS-c is one of the newly identified mitochondrial-derived peptides which play a role in regulating metabolic homeostasis. The current study aimed to investigate whether circulating MOTS-c levels are also associated with endothelial dysfunction(ED) in patients without significant structural coronary lesions. METHODS: Forty patients undergoing coronary angiography and endothelial function testing for clinical indications of recurrent angina with no structural coronary lesions were included in the study. They were divided into two groups based on coronary blood flow response to intracoronary acetylcholine (ACh) as normal endothelial function (≥ 50% increase from baseline) or ED, (n=20 each). Aortic plasma samples were collected at the time of catheterization for analysis of circulating MOTS-c levels by ELISA. The effect of MOTS-c on vascular reactivity was assessed in organ chambers using aortic rings collected from rats and renal artery stenosis (RAS) mice. RESULTS: Baseline characteristics were similar between the two groups. MOTS-c plasma levels were lower in patients with ED compared with patients with normal endothelial function (p=0.007). Furthermore, plasma MOTS-c levels were positively correlated with microvascular (p=0.01) and epicardial (p=0.02) coronary endothelial function. Although MOTS-c did not have direct vasoactive effects, pretreating aortic rings from rats or RAS mice with MOTS-c (2μg/ml) improved vessel responsiveness to ACh compared with vessels without MOTS-c treatment. CONCLUSION: Lower circulating endogenous MOTS-c levels in human subjects are associated with impaired coronary endothelial function. In rodents, MOTS-c improves endothelial function in vitro. Thus, MOTS-c represents a novel potential therapeutic target in patients with ED.
BACKGROUND:MOTS-c is one of the newly identified mitochondrial-derived peptides which play a role in regulating metabolic homeostasis. The current study aimed to investigate whether circulating MOTS-c levels are also associated with endothelial dysfunction(ED) in patients without significant structural coronary lesions. METHODS: Forty patients undergoing coronary angiography and endothelial function testing for clinical indications of recurrent angina with no structural coronary lesions were included in the study. They were divided into two groups based on coronary blood flow response to intracoronary acetylcholine (ACh) as normal endothelial function (≥ 50% increase from baseline) or ED, (n=20 each). Aortic plasma samples were collected at the time of catheterization for analysis of circulating MOTS-c levels by ELISA. The effect of MOTS-c on vascular reactivity was assessed in organ chambers using aortic rings collected from rats and renal artery stenosis (RAS) mice. RESULTS: Baseline characteristics were similar between the two groups. MOTS-c plasma levels were lower in patients with ED compared with patients with normal endothelial function (p=0.007). Furthermore, plasma MOTS-c levels were positively correlated with microvascular (p=0.01) and epicardial (p=0.02) coronary endothelial function. Although MOTS-c did not have direct vasoactive effects, pretreating aortic rings from rats or RAS mice with MOTS-c (2μg/ml) improved vessel responsiveness to ACh compared with vessels without MOTS-c treatment. CONCLUSION: Lower circulating endogenous MOTS-c levels in human subjects are associated with impaired coronary endothelial function. In rodents, MOTS-c improves endothelial function in vitro. Thus, MOTS-c represents a novel potential therapeutic target in patients with ED.
Authors: Marte Molenaars; Eileen G Daniels; Amber Meurs; Georges E Janssens; Riekelt H Houtkooper Journal: Philos Trans R Soc Lond B Biol Sci Date: 2020-05-04 Impact factor: 6.237